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Lessons Learned from Transient Remission Cases:

Clues to Biomarkers of HIV Rebound

Katherine Luzuriaga, MDUniversity of Massachusetts Medical School

Worcester, MA USA

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• New pediatric infections (MTCT) cut by 50% between 2001 and 2012: 900,000 new infections prevented since 2009

• 3.2 million children < 15 yrs living with HIV

• 1.5 million HIV-1+ women give birth each year; only ~68% receive ART for PMTCT

• 240, 000 children acquire HIV-1: one new infection every 2 minutes

UNAIDS, 2014

Global Eradication of Pediatric HIV-1 Infection

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Rationale for Early cART

• Rapid tempo of disease progression in HIV infected infants • Median viral loads > 105 copies/ml over first 2 years of life• High rates of viral production• Less robust adaptive HIV-specific immunity

• Ready identification of infants at risk and ability to make early nucleic acid-based rapid diagnosis

• Early cART reduces HIV-related morbidity and mortality (Violari et al, NEJM, 2008)• Early HIV diagnosis and cART are globally recommended as standard

of care

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Early cART restricts the latent reservoir

Persaud et al. AIDS, 2012

Restricted latent reservoir if treated < 6 wk (red circles) vs. > 6 wk (blue circles)

Reservoir decays over the first 2 yrs in early-treated infants (half-life 11 months [95% CI: 6 to 30 months]

Remains detectable in most (60%) at two years of age

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Lower PBMC DNA Levels In Children With Younger Age at Virologic Control

Persaud et al, JAMA Pediatr, 2014

Median 4.2 19 71

2-LTR DNA circles detectable in 20% of youth:

Proviral DNA copy number higher in those with detectable (median = 191) than in those with undetectable (median = 23) 2-LTR circles

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Clearance of HIV-specific Antibodies is a Hallmark of Early Effective cART in Infants

EIA negative at 15 months:

A. Durable HIV RNA suppression to < 400:

11 (73%) of 15 infants

B. Early tx, incomplete /transient suppression:

None (0%) of 5

C. HIV-uninfected infants born to HIV-infected women:

5 (100%) of 5

D. HIV- infected infants first treated > 12 mo:

None (0%) of 4

Luzuriaga et al, J Virol, 2000

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Low Proviral DNA Loads in Children with HIV-1 Negative or Indeterminate Wb

Persaud et al, JAMA Pediatr, 2014.

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Early and Very Early Therapy Restrict the Size and Modify the Persistence of HIV-1 Reservoirs

Luzuriaga, CROI, 2014; Persaud, CROI, 2015; Luzuriaga, JID, 2014; Persaud, JAMA Peds, 2014; Ananworanich, AIDS, 2014; van Zyl, JID, 2015; Bitnun, CID, 2014

Contribution to the proviral reservoir: TTM > TCM, EM

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HIV Remission Following Very Early cART

AZT/3TC/NVP

AZT/3TC/LPV/r

AZT/3TC/EFV

+RAL

ARV administered 31 hours - 18 months

Remission 28 months off cART

• No detectable HIV-1 in routine or scRNA assay • No replication-competent virus recovered• No detectable HIV-1 specific antibodies or CD4/CD8+ T cells• Absence of host factors associated with elite control

Viral Rebound at age 46 months

Persaud et al, NEJM, 2013; Luzuriaga, NEJM, 2015

SC RNA: 9 copies/ml

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HIV-1 rebound despite limited proviral and latent reservoirs

Bitnun, CID, 2014; Giacomet, PIDJ, 2014; Persaud, NEJM, 2014; Luzuriaga, NEJM, 2015; Vigano, J Peds, 2006

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Summary: Early/Very Early cART Alters HIV-1 Persistence in Children

• Limits proviral and replication competent reservoirs • Size correlated with the rapidity of control of

HIV replication • Decay rapidly over first year of therapy• Slower decay with prolonged suppression of

HIV replication • Decay in HIV proviral reservoirs over time in

absence of HIV-specific immune responses suggests that early cART limits infection of long-lived cells

• Contribution to the proviral reservoir: TTM > TCM, EM

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Markers for low-level proviral and latent reservoirs

• Plasma RNA below detection limits of single copy assays

• Lack of detectable 2 LTR DNA circles

• Absence of T cell activation • Lack of HIV-specific antibodies,

and CD4 and CD8+ T cell responses

Luzuriaga et al, J Virol, 2000;

Persaud et al, JAMA Peds, 2014; Ananworanich et al, AIDS, 2014

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Adults: 5-15% treated during PHI• On cART 12-192 mo (median 36 mo)• Remission off cART: 48-115 mo (median 89 mo)• Low level T cell activation and HIV-specific T cell

responses• Low circulating HIV-1 DNA levels (median 52 c/106

PBMC), with progressive decline over time in some

Pediatric case• Infected despite infant ARV prophylaxis• Received cART ~3 mo – 6 years• Plasma HIV-1 RNA < 50 for 12 years, except for

blips at 1, 2, 11, and 14 years; now < 4-9 c/ml• HIV-1 DNA 125-136 copies per million PBMC

Pathways to Remission: Post-Treatment Controllers

Saez-Cirion, PLoS Pathogens, 2013Saez-Cirion, IAS, 2015

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IMPAACT P1115: Very Early Intensive Treatment of HIV-Infected infants to achieve HIV remission: A proof of concept study

IMPAACT P1107: Cord Blood Transplantation with CCR5Δ32 Donor Cells in HIV-Infected Subjects who Require Bone Marrow Transplantation for any Indication and its Observed Effects on HIV-1 Persistence

Current Protocols

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Early/Very cART and HIV Persistence in Children

HIV positive infants and children with persistent suppression of HIV on cART are excellent candidates for additional strategies aimed at remission, particularly therapeutic vaccines:

• Normal immune responses• Absent HIV-specific immunity • Limited viral diversity

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Acknowledgements

Children and Families

Hannah Gay and Deborah Persaud

Persaud Lab: Carrie Ziemniak, Ya Hui Chen

Luzuriaga Lab: Margaret McManus, Linda Lambrecht, Joyce Pepe, Robin Brody, Keri Sanborn, Jim Coderre, Mohan Somasundaran

Collaborators: Matthew Strain, Danielle Murray, Douglas Richman, Tae-Wook Chun

Manuel Garber, Barbara Tabak Funding: NIAID, NICHD, AmFAR, JHU CFAR, UMMS CFAR, UMass Center for Clinical and Translational Science